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Year : 2018  |  Volume : 131  |  Issue : 8  |  Page : 950-955

Inhibitory Effects of Simvastatin on Oxidized Low-Density Lipoprotein-Induced Endoplasmic Reticulum Stress and Apoptosis in Vascular Endothelial Cells

1 Department of Emergency, China-Japan Friendship Hospital, Beijing 100029, China
2 Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
3 Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China

Correspondence Address:
Dr. Guo-Qiang Zhang
Department of Emergency, China-Japan Friendship Hospital, Beijing 100029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0366-6999.229891

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Background: Oxidized low-density lipoprotein (ox-LDL)-induced oxidative stress and endothelial apoptosis are essential for atherosclerosis. Our previous study has shown that ox-LDL-induced apoptosis is mediated by the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic translation initiation factor 2α-subunit (eIF2α)/CCAAT/enhancer-binding protein homologous protein (CHOP) endoplasmic reticulum (ER) stress pathway in endothelial cells. Statins are cholesterol-lowering drugs that exert pleiotropic effects including suppression of oxidative stress. This study aimed to explore the roles of simvastatin on ox-LDL-induced ER stress and apoptosis in endothelial cells. Methods: Human umbilical vein endothelial cells (HUVECs) were treated with simvastatin (0.1, 0.5, or 2.5 μmol/L) or DEVD-CHO (selective inhibitor of caspase-3, 100 μmol/L) for 1 h before the addition of ox-LDL (100 μg/ml) and then incubated for 24 h, and untreated cells were used as a control group. Apoptosis, expression of PERK, phosphorylation of eIF2α, CHOP mRNA level, and caspase-3 activity were measured. Comparisons among multiple groups were performed with one-way analysis of variance (ANOVA) followed by post hoc pairwise comparisons using Tukey's tests. A value of P < 0.05 was considered statistically significant. Results: Exposure of HUVECs to ox-LDL resulted in a significant increase in apoptosis (31.9% vs. 4.9%, P < 0.05). Simvastatin (0.1, 0.5, and 2.5 μmol/L) led to a suppression of ox-LDL-induced apoptosis (28.0%, 24.7%, and 13.8%, F = 15.039, all P < 0.05, compared with control group). Ox-LDL significantly increased the expression of PERK (499.5%, P < 0.05) and phosphorylation of eIF2α (451.6%, P < 0.05), if both of which in the control groups were considered as 100%. Simvastatin treatment (0.1, 0.5, and 2.5 μmol/L) blunted ox-LDL-induced expression of PERK (407.8%, 339.1%, and 187.5%, F = 10.121, all P < 0.05, compared with control group) and phosphorylation of eIF2α (407.8%, 339.1%, 187.5%, F = 11.430, all P < 0.05, compared with control group). In contrast, DEVD-CHO treatment had no significant effect on ox-LDL-induced expression of PERK (486.4%) and phosphorylation of eIF2α (418.8%). Exposure of HUVECs to ox-LDL also markedly induced caspase-3 activity together with increased CHOP mRNA level; these effects were inhibited by simvastatin treatment. Conclusions: This study suggested that simvastatin could inhibit ox-LDL-induced ER stress and apoptosis in vascular endothelial cells.


 Abstract in Chinese



方法:对人脐静脉内皮细胞使用辛伐他汀(0.1, 0.5, 2.5 μmol/L)及100 μmol/L的DEVD-CHO(特异性caspase-3抑制剂)孵育细胞1小时后,加入含100 μg/ml氧化型低密度脂蛋白的培养液孵育内皮细胞24小时,以未处理的细胞作为对照组;采用流式细胞仪检测内皮细胞凋亡率,采用Real-time PCR法检测CHOP mRNA的表达,采用比色法检测内皮细胞内caspase-3活性,采用western-blot法检测细胞内PERK蛋白表达及eIF2α蛋白的磷酸化。多组间比较采用单因素方差分析。
结果:与对照组(4.9%)相比,氧化型低密度脂蛋白培养内皮细胞24 小时显著增加内皮细胞凋亡率(31.9%), P<0.05,辛伐他汀(0.1 ,0.5,2.5 μmol/L)可减轻氧化型低密度脂蛋白诱导的内皮细胞凋亡(28.0%,24.7%,13.8%,F =15.039,相对于对照组,P<0.05)。以对照组为100%,氧化型低密度脂蛋白可显著增加PERK表达(499.5%,P<0.05)和eIF2α磷酸化水平(451.6%,P<0.05),而辛伐他汀(0.1,0.5,2.5 μmol/L)可抑制氧化型低密度脂蛋白诱导的PERK表达(477.4%,397.0%,194.0%,F = 10.121,相对于对照组,P <0.05)和eIF2α磷酸化水平(407.8%,339.1%,187.5%,F = 11.430,相对于对照组,P <0.05);而DEVD-CHO对于氧化型低密度脂蛋白诱导的PERK表达和eIF2α磷酸化水平无影响。另外,氧化型低密度脂蛋白可显著增强caspase-3活性,增加CHOP mRNA水平,而辛伐他汀可抑制此氧化型低密度脂蛋白诱导的上述效果。

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